Clinical trials with antiemetic agents in cancer patients receiving chemotherapy.

Vomiting accompanied by nausea is a serious acute toxicity which occurs after chemotherapy with virtually every class of cancer chemotherapeutic agents. The inability to adequately alleviate this toxicity may lead to serious complications such as general malaise, weight loss, and electrolyte imbalance. We have reviewed 34 studies in which more than 2200 cancer patients were administered 25 different antiemetics for treatment of chemotherapy-induced vomiting. All patients received a variety of cancer chemotherapeutic agents given either as single agents or in combination. The antiemetic agents included phenothiazines, antihistamines, anticholinergics, benzoquinolizines, barbiturates, butyrophenones, procainamides, cannabinoids, steroids, and benzodiazepines. It is apparent from these studies that the use of conventional antiemetic agents for treating cancer chemotherapy-induced vomiting is of marginal value, and the use of investigational antiemetic agents show conflicting results as to efficacy. More quantitative measures for evaluating emesis need to be defined, and the implications that a particular antiemetic therapy may be efficacious for some but not all classes of cancer chemotherapeutic agents need to be evaluated.

Current status of clinical trials of m-AMSA, dihydroxyanthracenedione, and deoxycoformycin.

The current status of three drugs of clinical interest to the National Cancer Institute is reviewed. m-AMSA, a drug with a wide spectrum of activity in murine tumors, is now in phase II trial and has shown itself to have a high order of activity in acute nonlymphocytic leukemia. Dihydroxyanthracenedione, a compound with some of the characteristics of anthracyclines but with no cardiac toxicity in animal toxicology studies, is in phase I evaluation. Deoxycoformycin, an adenosine analog which is a potent inhibitor of adenosine deaminase, has shown moderate activity in acute leukemia patients in phase I trials, and has the potential to produce synergistic antitumor toxicity when used with arabinofuranosyladenine.

PCNU: a new nitrosourea in clinical oncology.

PCNU is a new nitrosourea compound which has recently entered clinical trials. Preclinically it has been found to be effective against a variety of tumor models. Biochemically, PCNU was found to have optimal lipophilic, alkylating, and carbamoylating properties as compared to other nitrosourea agents. PCNU is able to diffuse into the CSF as demonstrated by pharmacokinetic studies. Clinical phase I studies indicate that the main toxicity is myelosuppression; nausea and vomiting were less frequently observed with PCNU than with other nitrosourea compounds. Human antitumor activity has been reported in a number of tumors, but most consistently in brain tumors. Phase II studies are now underway to confirm the antitumor activity of PCNU.

Current status of chemotherapy, hormonal therapy, and immunotherapy in the treatment of renal cell carcinoma.

Renal cell carcinoma is an uncommon but lethal disease. Since many patients initially present with metastatic disease and/or fail primary local therapy, therapeutic alternatives are needed. In our review of single agents none emerge as uniformly effective, although a number of chemotherapeutic agents are somewhat active, as is the hormonal agent, medroxyprogesterone. Combination chemotherapy, with and without hormonal agents and immunotherapeutics, appears to be somewhat more active, with several reports of CRs. Immunotherapeutic agents alone show promise in the limited studies reported to date. Several studies are now in progress, attempting to study new agents and combinations in this disease. Physicians are urged to participate in these studies.

Phase II study of 3-deazauridine in advanced colorectal adenocarcinoma.

A phase II study of 3-deazauridine (DAUR) showed poor activity in previously treated patients with advanced colorectal adenocarcinoma. There were no responses among 15 patients treated on a dose schedule of 1200 mg/m2/day for 5 days repeated at 3-week intervals. Toxicity included mild nausea and vomiting, occasional mucositis, diarrhea, and dizziness. A minimal degree of myelosuppression was observed.

Chemodectomas: review and report of nine cases.

We have reviewed the broad spectrum of disease caused by chemodectomas. This spectrum extends from the benign to the aggressively malignant with many graduations in-between. Our analyses included cases from the literature and nine new cases seen over the past twenty-five years. Surgery as the primary and most definitive form of therapy, is recommended if feasible, with total excision as the goal, in both benign and malignant histologies. An excellent outcome is to be expected in benign cases. At present, no predictor exists to foretell the behavior of malignant lesions, which can range from the aggressive to the slowly progressive. Both radiotherapy and chemotherapy have been tried in malignant cases. No consistent good result has occurred from the use of either. The future will hopefully bring us more effective therapy.

Indicine-N-oxide: a new antitumor agent.

Indicine-N-oxide, a pyrrolizidine derivative, was selected for development because of activity in the murine P388 leukemia model. Route and schedule dependency have been demonstrated. It is believed that the antitumor activity of the drug is mediated via antimitotic effects and chromosomal damage. However, the active metabolic species responsible for these antitumor properties is not yet known. The major toxic effect was myelosuppression. Phase I clinical trials have arrived at recommended doses for further study. Colon carcinoma has been found to be possibly responsive, and several tumor types were reported stable during phase I testing. In a single phase II study in refractory leukemia, there were three responses, including one complete response, among seven patients. Phase II studies in all panel tumors are indicated, especially colon carcinoma and leukemias.

ICRF-187 in clinical oncology.

Although the mechanism of action of ICRF-159 and 187 has not been clearly defined, it is evident from both preclinical and early clinical studies that these compounds are of interest. There are three distinct characteristics of these ICRF compounds that deserve careful clinical evaluation. First, these drugs are apparently alkylating agents with modest, predictable and noncumulative bone marrow toxicity that makes them good potential candidates for combination chemotherapy regimens. The second characteristic that should be investigated is the suggestion that combination of ICRF-187 with an anthracycline may ameliorate the cardiac toxicity of the latter. The third factor in the preclinical evaluation of the bis-diketopiperazines that may have clinical application is the evidence that suggests that these drugs have an antimetastatic effect.

delta 9-tetrahydrocannabinol in clinical oncology.

After anecdotal reports of marijuana's providing antiemetic activity in cancer chemotherapy patients refractory to standard agents, orally administered delta 9-tetrahydrocannabinol (THC) was formally studied by a number of investigators. In six of seven well-controlled studies, orally administered THC was a superior antiemetic agent compared with control agents. The THC toxic effects are notable but manageable. Patients rarely require hospitalization after the development of THC-induced dysphorias. However, serious toxic effects are uncommon and the most frequently noted effects are somnolence, conjunctivitis, and tachycardias. Because certain subgroups of patients are more prone to have toxicities develop, careful selection of the candidates to receive this agent is mandatory. Overall, the benefits of orally administered THC use represent a major advance in antiemetic therapy.

Bis-diketopiperazine derivatives in clinical oncology: ICRF-159.

ICRF-159 is a bis-diketopiperazine derivative active in a variety of preclinical animal tumor models. Because of its poor solubility characteristics, the drug must be given p.o. However, when given by this route at high doses, poor bioavailability was noted. Two interesting preclinical properties of this agent are its antimetastatic effect and the ability to reduce anthracycline cardiotoxicity. Phase I studies have delineated myelosuppression as the major toxicity with GI toxicity also occurring. In phase II studies, interesting activity has been noted in lymphomas and head and neck carcinomas. When ICRF-159 was combined with radiotherapy, prolonged responses were noted in sarcoma and lung carcinoma in small numbers of patients. Further studies are indicated in areas of activity as a single agent and as a potentiator of radiation therapy.

2'-deoxycoformycin. A new anticancer agent.

2'-deoxycoformycin (2'-dCF) is a powerful inhibitor of adenosine deaminase (ADA), an enzyme found in high concentrations in lymphoid tissue. Although inactive in preclinical tumor models, 2'-dCF has shown clinical antitumor activity as a single agent in lymphoid malignancies. This drug has the added potential of being useful as a potentiator of other antitumor agents which are deactivated by ADA. It is also possible that the drug has potential as an immunosuppressive agent. Phase I studies are ongoing and phase II trials are planned to define the antitumor spectrum of this agent.

Current status of chemotherapy in the treatment of advanced carcinoma of the thyroid gland.

An extensive review of the literature was undertaken to identify single agents and chemotherapeutic combinations active against advanced thyroid carcinoma. The two most intensively studied agents were Adriamycin and bleomycin, both of which appear to have definite activity against advanced disease. Studies of 25 other single agents and 17 drug combinations were also reviewed but most of the studies suffered from extremely poor patient accrual, thus precluding statistical analysis. Two cooperative group protocols are in progress which will hopefully accrue enough patients for meaningful interpretation. Physicians treating advanced thyroid carcinoma patients are urged to participate in these studies.

Acivicin. An antitumor antibiotic.

Acivicin [(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including the L1210 and P388 leukemias, the M5076 ovarian carcinoma, and the MX-1 human breast tumor xenograft. Antitumor activity is probably mediated through the inhibition of enzymes catalyzing amido transfer from L-glutamine, especially CTP synthetase and XMP aminase. In mice, acivicin is absorbed systemically via the p.o., I.P., and S.C. routes and is predominantly excreted in the urine in unchanged form. Although a wide variety of toxicities, including myelosuppression, were noted in dogs and monkeys, vomiting, diarrhea, and pathologic lesions of the GI tract predominated in both species. A marked cumulative toxicity was noted in dogs with 16 mg/m2/day being the lethal dose on the daily x 5 schedule compared to 1000 mg/m2 on the single-dose schedule. An interesting phenomenon was noted in mice wherein older male mice were more resistant to the toxic effects of the drug than female or younger male mice. This sex and age difference in susceptibility to acivicin toxicity was shown to be correlated with differences in pharmacokinetics; older male mice cleared acivicin at approximately twice the rate of females or younger males. No sex differences in toxicity were noted in dogs or monkeys. Because of its activity in mouse tumor systems and acceptable preclinical toxicology patterns, the drug is being introduced into clinical phase I studies under the sponsorship of the National Cancer Institute.